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Article(id=1322954406559363635, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1322954308836270447, articleNumber=null, orderNo=null, doi=10.16016/j.2097-0927.202507094, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1753632000000, receivedDateStr=2025-07-28, revisedDate=1761148800000, revisedDateStr=2025-10-23, acceptedDate=null, acceptedDateStr=null, onlineDate=1793346509827, onlineDateStr=2026-10-30, pubDate=1763136000000, pubDateStr=2025-11-15, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1793346509827, onlineIssueDateStr=2026-10-30, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1793346509827, creator=13701087609, updateTime=1793346509827, updator=13701087609, issue=Issue{id=1322954308836270447, tenantId=1146029695717560320, journalId=1319373162502258839, year='2025', volume='47', issue='21', pageStart='2581', pageEnd='2724', issueExtLink='null', onlineDate='null', pubDate='1763136000000', pubDateStr='2025-11-15', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1793346486529, creator='13701087609', updateTime=1793346486529, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext=null, issueFiles=null, downloadFileDto=null}, startPage=2652, endPage=2662, ext={EN=ArticleExt(id=1322954406857159220, articleId=1322954406559363635, tenantId=1146029695717560320, journalId=1319373162502258839, language=EN, title=GenX induces cochlear hair cell injury via System Xc⁻-Gpx4-Fsp1 ferroptosis axis, columnId=1320434418116837551, journalTitle=Journal of Army Medical University, columnName=Basic Medicine, runingTitle=null, highlight=null, articleAbstract=
Objective

To investigate the role and mechanism of ferroptosis in cochlear hair cell injury induced by exposure to ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoate (GenX).

Methods

Mouse cochlear hair cell line HEI-OC1 was assigned to control, GenX, ferrostatin-1 (Fer-1), and GenX+Fer-1 groups. CCK-8 assay was used to assess the cytotoxicity of GenX and the rescue effect of Fer-1 co-treatment. Western blotting and qRT-PCR were employed to measure the protein and transcriptional expression of ferroptosis markers, cochlear function indicators, blood labyrinth barrier markers, and ferroptosis-related pathway. FerroOrange, Bodipy(C11), mitochondrial membrane potential assay kit (JC-1), and adenosine triphosphate (ATP) assay were applied to detect Fe²⁺ accumulation, lipid peroxidation, mitochondrial membrane dysfunction, and cellular ATP levels, respectively.

Results

Exposure to 200 μmol/L GenX for 12 h significantly reduced the viability of HEI-OC1 cells (P<0.01), down-regulated the protein levels of glutathione peroxidase 4 (Gpx4), solute carrier family 7 member 11 (Slc7a11), and ferroptosis suppressor protein 1 (Fsp1) (P<0.05), whereas up-regulated acyl-coa synthetase long-chain family member 4 (Acsl4) (P<0.01), and decreased the expression of cochlear hair-cell function genes and blood labyrinth barrier genes (P<0.05). These changes were accompanied with Fe2+ accumulation, elevated lipid peroxidation, mitochondrial membrane damage, and reduced ATP production (P<0.001). Addition of Fer-1 restored cell viability (P<0.05), restored the expression of ferroptosis related proteins (P<0.05), and improved the expression of several hair-cell function and blood labyrinth barrier genes (P<0.05). In parallel, the GenX+Fer-1 group exhibited reduced Fe²⁺ accumulation, lower lipid peroxidation, attenuated mitochondrial membrane damage, and increased ATP level (P<0.001).

Conclusion

GenX induces iron-metabolism dysregulation and lipid peroxidation, and then leads to differentiation impairment of cochlear hair cells and barrier functions via the ferroptotic System Xc⁻-Gpx4-Fsp1 axis.

, authors=Zhengwei LIANG1, 2, Huihui HONG3, Wei YUAN1, 2, authorsList=Zhengwei LIANG, Huihui HONG, Wei YUAN, authorCompany=null, correspAuthors=Wei YUAN, authorNote=null, correspAuthorsNote=null, copyrightStatement=© 2025 Journal of Army Medical University, copyrightOwner=Editorial Office of Journal of Army Medical University, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1322954412095844930, articleId=1322954406559363635, tenantId=1146029695717560320, journalId=1319373162502258839, language=CN, title=GenX通过System Xc⁻-Gpx4-Fsp1铁死亡轴诱导耳蜗毛细胞损伤, columnId=1320434418343329969, journalTitle=陆军军医大学学报, columnName=论著·基础医学, runingTitle=null, highlight=null, articleAbstract=
目的

探讨铁死亡在2，3，3，3-四氟-2-（七氟丙氧基）丙酸铵［ammonium 2，3，3，3-tetrafluoro-2-（heptafluoropropoxy）-propanoate，GenX］暴露诱导耳蜗毛细胞损伤中的作用与机制。

方法

体外培养HEI-OC1细胞，分为对照组、GenX组、铁死亡抑制剂（ferrostatin-1，Fer-1）组、GenX+Fer-1组，CCK-8检测GenX对耳蜗毛细胞的毒性作用，CCK-8检测GenX+Fer-1共处理后观察有无铁死亡的发生，Western blot和qRT-PCR检测铁死亡标志物、耳蜗分化功能指标、耳血迷路屏障标志物和听力相关铁死亡通路蛋白和基因的表达，使用FerroOrange、Bodipy（C11）、线粒体膜电位荧光探针（mitochondrial membrane potential assay kit，JC-1）和ATP探针分别检测Fe²⁺蓄积、脂质过氧化水平、线粒体膜损伤和ATP情况。

结果

200 μmol/L GenX暴露12 h后显著降低HEI-OC1细胞活力（P<0.01）。GenX暴露12 h后引起磷脂氢过氧化物谷胱甘肽过氧化物酶（phospholipid hydroperoxide glutathione peroxidase，Gpx4）、溶质载体家族7成员11和铁死亡抑制蛋白1（ferroptosis suppressor protein 1，Fsp1）蛋白表达下调（P<0.05），酰基辅酶A合成酶长链家族成员4蛋白表达上调（P<0.01），耳蜗毛细胞分化功能基因和耳血迷路屏障基因表达降低（P<0.05），同时伴随Fe²⁺蓄积、脂质过氧化水平升高和线粒体膜损伤及降低ATP生成（P<0.001）。GenX+Fer-1组可显著恢复细胞活力（P<0.05），逆转铁死亡蛋白的表达（P<0.05），并改善部分耳蜗分化功能基因和耳血迷路屏障基因的表达（P<0.05）。同时GenX+Fer-1组可减少Fe²⁺蓄积、降低脂质过氧化水平、抑制线粒体膜损伤和升高ATP水平（P<0.001）。

结论

GenX通过诱导铁代谢紊乱、脂质过氧化蓄积，并依赖System Xc⁻-Gpx4-Fsp1铁死亡轴途径损伤耳蜗毛细胞的分化和屏障功能。

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袁伟，E-mail：
YUAN Wei，E-mail：
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Arch Toxicol，2024，98（3）：579-615., articleTitle=Ferroptosis regulation through Nrf2 and implications for neurodegenerative diseases, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1322954413974893123, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, xref=1, ext=[AuthorCompanyExt(id=1322954414008447556, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, companyId=1322954413974893123, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Otolaryngology-Head and Neck Surgery，the Affiliated Hospital of Southwest Medical University，Luzhou，Sichuan), AuthorCompanyExt(id=1322954414042001989, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, companyId=1322954413974893123, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1西南医科大学附属医院耳鼻咽喉头颈外科，四川 泸州)]), AuthorCompany(id=1322954414176219718, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, xref=2, ext=[AuthorCompanyExt(id=1322954414184608327, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, companyId=1322954414176219718, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2Department of Otolaryngology-Head and Neck Surgery，Chongqing General Hospital （Chongqing University Affiliated People’s Hospital），Chongqing), AuthorCompanyExt(id=1322954414197191240, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, companyId=1322954414176219718, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2重庆市人民医院（重庆大学附属人民医院）耳鼻咽喉头颈外科，重庆)]), AuthorCompany(id=1322954414289465929, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, xref=3, ext=[AuthorCompanyExt(id=1322954414297854538, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, companyId=1322954414289465929, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3Neuro-Intelligence Center Laboratory，Chongqing University School of Medicine，Chongqing，China), AuthorCompanyExt(id=1322954414306243147, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, companyId=1322954414289465929, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3重庆大学医学院神经智能中心实验室，重庆)])], figs=[ArticleFig(id=1322954419662369387, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, language=EN, label=Figure 1, caption=Cell viability of cochlear hair cells exposed to 50，100 and 200 μmol/L GenX for 12，24，36，48，60 and 72 h, figureFileSmall=cE5baB937Qq8vrhMh+KblA==, figureFileBig=WBvS2MSbeszY97Gr6bm/eg==, tableContent=null), ArticleFig(id=1322954419733672556, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, language=CN, label=图1, caption=50、100、200 μmol/L GenX 暴露耳蜗毛细胞12、24、36、48、60、72 h后的细胞活力图

a：P<0.05，b：P<0.01，c：P<0.001，compared with the Control

, figureFileSmall=cE5baB937Qq8vrhMh+KblA==, figureFileBig=WBvS2MSbeszY97Gr6bm/eg==, tableContent=null), ArticleFig(id=1322954419960164973, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, language=EN, label=Figure 2, caption=GenX exposure induces ferroptosis in cochlear hair cells, figureFileSmall=vbqLzCha5yXryAiNq8eicg==, figureFileBig=RVbFt70CukmlL/2hi/jk0w==, tableContent=null), ArticleFig(id=1322954420031468142, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, language=CN, label=图2, caption=GenX暴露引起耳蜗毛细胞铁死亡的发生

A：Viability of HEI-OC1 cells treated with different concentrations of Fer-1； B：Viability of HEI-OC1 cells across Control，GenX，Fer-1，and GenX+Fer-1 groups； C：ATP levels in HEI-OC1 cells； D：Representative images of FerroOrange fluorescence staining in HEI-OC1 cells. a：P<0.05，b：P<0.01，c：P<0.001

, figureFileSmall=vbqLzCha5yXryAiNq8eicg==, figureFileBig=RVbFt70CukmlL/2hi/jk0w==, tableContent=null), ArticleFig(id=1322954420106965615, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, language=EN, label=Figure 2（continued）, caption=GenX exposure induces ferroptosis in cochlear hair cells, figureFileSmall=AX2SgZBPmzRc2YMQ3+eS2A==, figureFileBig=Im4AyL4R/TgfraWf1HAugA==, tableContent=null), ArticleFig(id=1322954420169880176, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, language=CN, label=续图2, caption=GenX暴露引起耳蜗毛细胞铁死亡的发生

E：Representative images of Bodipy（C11） fluorescence staining in HEI-OC1 cells； F：Representative images of JC-1 fluorescence staining in HEI-OC1 cells

, figureFileSmall=AX2SgZBPmzRc2YMQ3+eS2A==, figureFileBig=Im4AyL4R/TgfraWf1HAugA==, tableContent=null), ArticleFig(id=1322954420241183345, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, language=EN, label=Figure 3, caption=Changes in key molecules of the ferroptosis pathway in cochlear hair cells exposed to GenX, figureFileSmall=WG+stnoBZ2xZigJFWzUh+w==, figureFileBig=y9fBCMDqnU12mUdnb9yWnQ==, tableContent=null), ArticleFig(id=1322954420325069426, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, language=CN, label=图3, caption=GenX诱导耳蜗毛细胞铁死亡途径中关键分子变化

A：Schematic diagram of transmission mechanism of key molecules in the ferroptosis pathway； B：Relative mRNA levels of ferroptosis-related genes in HEI-OC1 cells； C and D：Protein expression levels and statistical analysis of Gpx4，Acsl4，and Slc7a11 in HEI-OC1 cells. a：P<0.05，b：P<0.01，c： P<0.001

, figureFileSmall=WG+stnoBZ2xZigJFWzUh+w==, figureFileBig=y9fBCMDqnU12mUdnb9yWnQ==, tableContent=null), ArticleFig(id=1322954420396372595, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, language=EN, label=Figure 4, caption=Fer-1 protects cochlear hair cells against GenX-induced functional impairment, figureFileSmall=vj/Ww4VphCpR+NUxZJSp1w==, figureFileBig=9jzsT2hLTzgJzzG5UBqzGQ==, tableContent=null), ArticleFig(id=1322954420467675764, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, language=CN, label=图4, caption=Fer-1能抵抗GenX对耳蜗毛细胞功能损伤

A：Relative mRNA expression levels of self-differentiation-related genes in HEI-OC1 cells； B：Relative mRNA expression levels of blood-labyrinth barrier-related genes in HEI-OC1 cells； C：Representative images of Myo7a and Claudin5 protein expression in HEI-OC1 cells； D：Statistical analysis of Myo7a and Claudin5 protein expression levels in HEI-OC1 cells. a：P<0.05，b：P<0.01，c：P<0.001

, figureFileSmall=vj/Ww4VphCpR+NUxZJSp1w==, figureFileBig=9jzsT2hLTzgJzzG5UBqzGQ==, tableContent=null), ArticleFig(id=1322954420543173237, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, language=EN, label=Figure 5, caption=Fer-1 reverses GenX-induced disruption of the ferroptosis-associated auditory pathway in cochlear hair cells, figureFileSmall=WjJ20+HiOZmo9cFPyKZKXw==, figureFileBig=vwJ0tpx2xtZ31f4PT2hOvA==, tableContent=null), ArticleFig(id=1322954420601893494, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, language=CN, label=图5, caption=Fer-1能逆转GenX暴露引起的耳蜗毛细胞铁死亡-听力损伤信号通路

A：Relative mRNA expression levels of genes in the Fsp1-Coq10-Nadph signaling pathway in HEI-OC1 cells； B：Relative mRNA expression levels of genes in the Lkb1-AMPK signaling pathway in HEI-OC1 cells； C：Relative mRNA expression levels of genes in the Nrf2-Ho1 signaling pathway in HEI-OC1 cells； D：Representative image of Fsp1 protein expression in HEI-OC1 cells； E：Statistical analysis of Fsp1 protein expression across groups in HEI-OC1 cells. a：P<0.05，b：P<0.01，c：P<0.001

, figureFileSmall=WjJ20+HiOZmo9cFPyKZKXw==, figureFileBig=vwJ0tpx2xtZ31f4PT2hOvA==, tableContent=null), ArticleFig(id=1322954420677390967, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, language=EN, label=Table 1, caption=

Primer sequences for qRT-PCR

, figureFileSmall=null, figureFileBig=null, tableContent=
GenesSequences（5’→3’）
OccludinForward primer：TTGAAAGTCCACCTCCTTACAGA
Reverse primer：CCGGATAAAAAGAGTACGCTGG
ZO-1Forward primer：GGACAGAGCCTATGGAACGG
Reverse primer：CACCAAGGAAGCGATGAAGC
Claudin5Forward primer：GCAAGGTGTATGAATCTGTGCT
Reverse primer：GTCAAGGTAACAAAGAGTGCCA
CldnbForward primer：CTCTTGAGCAGCATCCTCACA
Reverse primer：GCCTCTCGACACTGAATCCTT
Myo7aForward primer：CACCAAGGGAGATTGTGGCC
Reverse primer：CCTTGGACACCATGACACGG
Slc26a5Forward primer：GAAAGGCCCATCTTCAGTCATC
Reverse primer：GCCACTTAGTGATAGGCAGGAAC
AmpkForward primer：TCTGAGGGGCACCAAGAAAC
Reverse primer：GTGGGTGTTGACGGAGAAGAG
Lkb1Forward primer：TTCAACCGAGTGGGTTATTTTGT
Reverse primer：TACTGGGCATCTGGGGTGTAG
Nrf2Forward primer：ACACGAGATGAGCTTAGGGC
Reverse primer：TCGGATCAATGCGAGCTGAG
Fsp1Forward primer：ACATCAAGGTGGAAACGGACAAG
Reverse primer：GCGGTAGGCAGAGCTGTTAATC
Coq10Forward primer：CAGCTCGGACCAGTCAGAG
Reverse primer：TCCTCCATTCCTGATACTACGTC
Ho1Forward primer：CTGTCCAGTTGGTGTGGATAA
Reverse primer：TCAGGCAGAGGGTGATAGAA
NadphForward primer：CAACGCACAGGCTCAAATGG
Reverse primer：CACTCTCGTTCAGAATCCAGC
Acsl4Forward primer：CATATCGCTCTGTCACGCACTTC
Reverse primer：GGCTGTCCTTCTTCCCAAACTTG
Gpx4Forward primer：GATGGAGCCCATTCCTGAACC
Reverse primer：CCCTGTACTTATCCAGGCAGA
Slc7a11Forward primer：TGTGTTCGCTGTCTCCAGGTTATTC
Reverse primer：GAGAAGAGCATCACCATCGTCAGAG
Lpcat3Forward primer：GACGGGGACATGGGAGAGA
Reverse primer：GTAAAACAGAGCCAACGGGTAG
mGpx4Forward primer：ATGAGCTGGGGCCGTCTG
Reverse primer：CCCTGTACTTATCCAGGCAGACC
Slc3a2Forward primer：TGATGAATGCACCCTTGTACTTG
Reverse primer：GCTCCCCAGTGAAAGTGGA
ActbForward primer：GGCTGTATTCCCCTCCATCG
Reverse primer：CCAGTTGGTAACAATGCCATGT
), ArticleFig(id=1322954420748694136, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954406559363635, language=CN, label=表1, caption=

qRT-PCR引物

, figureFileSmall=null, figureFileBig=null, tableContent=
GenesSequences（5’→3’）
OccludinForward primer：TTGAAAGTCCACCTCCTTACAGA
Reverse primer：CCGGATAAAAAGAGTACGCTGG
ZO-1Forward primer：GGACAGAGCCTATGGAACGG
Reverse primer：CACCAAGGAAGCGATGAAGC
Claudin5Forward primer：GCAAGGTGTATGAATCTGTGCT
Reverse primer：GTCAAGGTAACAAAGAGTGCCA
CldnbForward primer：CTCTTGAGCAGCATCCTCACA
Reverse primer：GCCTCTCGACACTGAATCCTT
Myo7aForward primer：CACCAAGGGAGATTGTGGCC
Reverse primer：CCTTGGACACCATGACACGG
Slc26a5Forward primer：GAAAGGCCCATCTTCAGTCATC
Reverse primer：GCCACTTAGTGATAGGCAGGAAC
AmpkForward primer：TCTGAGGGGCACCAAGAAAC
Reverse primer：GTGGGTGTTGACGGAGAAGAG
Lkb1Forward primer：TTCAACCGAGTGGGTTATTTTGT
Reverse primer：TACTGGGCATCTGGGGTGTAG
Nrf2Forward primer：ACACGAGATGAGCTTAGGGC
Reverse primer：TCGGATCAATGCGAGCTGAG
Fsp1Forward primer：ACATCAAGGTGGAAACGGACAAG
Reverse primer：GCGGTAGGCAGAGCTGTTAATC
Coq10Forward primer：CAGCTCGGACCAGTCAGAG
Reverse primer：TCCTCCATTCCTGATACTACGTC
Ho1Forward primer：CTGTCCAGTTGGTGTGGATAA
Reverse primer：TCAGGCAGAGGGTGATAGAA
NadphForward primer：CAACGCACAGGCTCAAATGG
Reverse primer：CACTCTCGTTCAGAATCCAGC
Acsl4Forward primer：CATATCGCTCTGTCACGCACTTC
Reverse primer：GGCTGTCCTTCTTCCCAAACTTG
Gpx4Forward primer：GATGGAGCCCATTCCTGAACC
Reverse primer：CCCTGTACTTATCCAGGCAGA
Slc7a11Forward primer：TGTGTTCGCTGTCTCCAGGTTATTC
Reverse primer：GAGAAGAGCATCACCATCGTCAGAG
Lpcat3Forward primer：GACGGGGACATGGGAGAGA
Reverse primer：GTAAAACAGAGCCAACGGGTAG
mGpx4Forward primer：ATGAGCTGGGGCCGTCTG
Reverse primer：CCCTGTACTTATCCAGGCAGACC
Slc3a2Forward primer：TGATGAATGCACCCTTGTACTTG
Reverse primer：GCTCCCCAGTGAAAGTGGA
ActbForward primer：GGCTGTATTCCCCTCCATCG
Reverse primer：CCAGTTGGTAACAATGCCATGT
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GenX通过System Xc⁻-Gpx4-Fsp1铁死亡轴诱导耳蜗毛细胞损伤
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梁正薇 1, 2 , 洪慧慧 3 , 袁伟 1, 2
陆军军医大学学报 | 论著·基础医学 2025,47(21): 2652-2662
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陆军军医大学学报 |论著·基础医学 2025 , 47 (21) : 2652 -2662
GenX通过System Xc⁻-Gpx4-Fsp1铁死亡轴诱导耳蜗毛细胞损伤
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梁正薇1, 2, 洪慧慧3, 袁伟1, 2
作者信息
  • 1西南医科大学附属医院耳鼻咽喉头颈外科，四川 泸州
  • 2重庆市人民医院（重庆大学附属人民医院）耳鼻咽喉头颈外科，重庆
  • 3重庆大学医学院神经智能中心实验室，重庆
通讯作者:
袁伟，E-mail：
YUAN Wei，E-mail：
GenX induces cochlear hair cell injury via System Xc⁻-Gpx4-Fsp1 ferroptosis axis
Zhengwei LIANG1, 2, Huihui HONG3, Wei YUAN1, 2
Affiliations
  • 1Department of Otolaryngology-Head and Neck Surgery，the Affiliated Hospital of Southwest Medical University，Luzhou，Sichuan
  • 2Department of Otolaryngology-Head and Neck Surgery，Chongqing General Hospital （Chongqing University Affiliated People’s Hospital），Chongqing
  • 3Neuro-Intelligence Center Laboratory，Chongqing University School of Medicine，Chongqing，China
出版时间: 2025-11-15 doi: 10.16016/j.2097-0927.202507094
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摘要
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目的

探讨铁死亡在2，3，3，3-四氟-2-（七氟丙氧基）丙酸铵［ammonium 2，3，3，3-tetrafluoro-2-（heptafluoropropoxy）-propanoate，GenX］暴露诱导耳蜗毛细胞损伤中的作用与机制。

方法

体外培养HEI-OC1细胞，分为对照组、GenX组、铁死亡抑制剂（ferrostatin-1，Fer-1）组、GenX+Fer-1组，CCK-8检测GenX对耳蜗毛细胞的毒性作用，CCK-8检测GenX+Fer-1共处理后观察有无铁死亡的发生，Western blot和qRT-PCR检测铁死亡标志物、耳蜗分化功能指标、耳血迷路屏障标志物和听力相关铁死亡通路蛋白和基因的表达，使用FerroOrange、Bodipy（C11）、线粒体膜电位荧光探针（mitochondrial membrane potential assay kit，JC-1）和ATP探针分别检测Fe²⁺蓄积、脂质过氧化水平、线粒体膜损伤和ATP情况。

结果

200 μmol/L GenX暴露12 h后显著降低HEI-OC1细胞活力（P<0.01）。GenX暴露12 h后引起磷脂氢过氧化物谷胱甘肽过氧化物酶（phospholipid hydroperoxide glutathione peroxidase，Gpx4）、溶质载体家族7成员11和铁死亡抑制蛋白1（ferroptosis suppressor protein 1，Fsp1）蛋白表达下调（P<0.05），酰基辅酶A合成酶长链家族成员4蛋白表达上调（P<0.01），耳蜗毛细胞分化功能基因和耳血迷路屏障基因表达降低（P<0.05），同时伴随Fe²⁺蓄积、脂质过氧化水平升高和线粒体膜损伤及降低ATP生成（P<0.001）。GenX+Fer-1组可显著恢复细胞活力（P<0.05），逆转铁死亡蛋白的表达（P<0.05），并改善部分耳蜗分化功能基因和耳血迷路屏障基因的表达（P<0.05）。同时GenX+Fer-1组可减少Fe²⁺蓄积、降低脂质过氧化水平、抑制线粒体膜损伤和升高ATP水平（P<0.001）。

结论

GenX通过诱导铁代谢紊乱、脂质过氧化蓄积，并依赖System Xc⁻-Gpx4-Fsp1铁死亡轴途径损伤耳蜗毛细胞的分化和屏障功能。

铁死亡  /  2，3，3，3-四氟-2-（七氟丙氧基）丙酸铵  /  磷脂氢过氧化物谷胱甘肽过氧化物酶  /  铁死亡抑制蛋白1  /  耳蜗毛细胞
Objective

To investigate the role and mechanism of ferroptosis in cochlear hair cell injury induced by exposure to ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoate (GenX).

Methods

Mouse cochlear hair cell line HEI-OC1 was assigned to control, GenX, ferrostatin-1 (Fer-1), and GenX+Fer-1 groups. CCK-8 assay was used to assess the cytotoxicity of GenX and the rescue effect of Fer-1 co-treatment. Western blotting and qRT-PCR were employed to measure the protein and transcriptional expression of ferroptosis markers, cochlear function indicators, blood labyrinth barrier markers, and ferroptosis-related pathway. FerroOrange, Bodipy(C11), mitochondrial membrane potential assay kit (JC-1), and adenosine triphosphate (ATP) assay were applied to detect Fe²⁺ accumulation, lipid peroxidation, mitochondrial membrane dysfunction, and cellular ATP levels, respectively.

Results

Exposure to 200 μmol/L GenX for 12 h significantly reduced the viability of HEI-OC1 cells (P<0.01), down-regulated the protein levels of glutathione peroxidase 4 (Gpx4), solute carrier family 7 member 11 (Slc7a11), and ferroptosis suppressor protein 1 (Fsp1) (P<0.05), whereas up-regulated acyl-coa synthetase long-chain family member 4 (Acsl4) (P<0.01), and decreased the expression of cochlear hair-cell function genes and blood labyrinth barrier genes (P<0.05). These changes were accompanied with Fe2+ accumulation, elevated lipid peroxidation, mitochondrial membrane damage, and reduced ATP production (P<0.001). Addition of Fer-1 restored cell viability (P<0.05), restored the expression of ferroptosis related proteins (P<0.05), and improved the expression of several hair-cell function and blood labyrinth barrier genes (P<0.05). In parallel, the GenX+Fer-1 group exhibited reduced Fe²⁺ accumulation, lower lipid peroxidation, attenuated mitochondrial membrane damage, and increased ATP level (P<0.001).

Conclusion

GenX induces iron-metabolism dysregulation and lipid peroxidation, and then leads to differentiation impairment of cochlear hair cells and barrier functions via the ferroptotic System Xc⁻-Gpx4-Fsp1 axis.

ferroptosis  /  ammonium 2，3，3，3-tetrafluoro-2-（heptafluoropropoxy）-propanoate  /  phospholipid hydroperoxide glutathione peroxidase  /  ferroptosis suppressor protein 1  /  cochlear hair cells
梁正薇, 洪慧慧, 袁伟. GenX通过System Xc⁻-Gpx4-Fsp1铁死亡轴诱导耳蜗毛细胞损伤. 陆军军医大学学报, 2025 , 47 (21) : 2652 -2662 . DOI: 10.16016/j.2097-0927.202507094
Zhengwei LIANG, Huihui HONG, Wei YUAN. GenX induces cochlear hair cell injury via System Xc⁻-Gpx4-Fsp1 ferroptosis axis[J]. Journal of Army Medical University, 2025 , 47 (21) : 2652 -2662 . DOI: 10.16016/j.2097-0927.202507094
正文
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听力损失（hearing loss，HL）正逐渐成为全球公共卫生领域面临的严重挑战［1］。据世界卫生组织（World Health Organization，WHO）统计，全球约有超过5%的人口患有HL［2］。与正常人相比，HL患者容易出现认知功能下降、社会孤立及心理健康问题［3］。耳蜗毛细胞是听觉信号传导的核心结构，具有不可再生性，HEI-OC1细胞系源自新生小鼠耳蜗柯蒂氏器，同时该细胞系对耳毒性药物敏感，因而被广泛用于研究毛细胞损伤机制及筛选耳保护药物［4］。
2，3，3，3-四氟-2-（七氟丙氧基）丙酸铵［ammonium 2，3，3，3-tetrafluoro-2-（heptafluoropropoxy）-propanoate，GenX］是为替代传统的全氟辛酸（perfluorooctanoic acid，PFOA）而开发的一种新型全氟化合物，具有优良的化学稳定性和水溶性，常被用于半导体、航空航天及不粘涂层生产［5］。研究表明，GenX可通过工业废水排放、大气沉降及土壤渗透进入生态环境［6］。据相关研究推算，我国部分主要河流流域的GenX排放量达到数吨级别［7］。近年来，关于GenX毒性的研究逐步增多，不仅可引发肝脏损伤，还影响生殖神经系统功能［6］。然而，目前关于GenX对听觉系统的潜在危害仍缺乏明确证据。
铁死亡是2012年首次定义的一种依赖铁元素的程序性细胞死亡形式，其核心特征包括谷胱甘肽（glutathione，GSH）水平下降、磷脂氢过氧化物谷胱甘肽过氧化物酶（phospholipid hydroperoxide glutathione peroxidase，Gpx4）活性降低、脂质过氧化积累及Fe²⁺超载［8］。溶质载体家族7成员11（solute carrier family 7 member 11，Slc7a11）和溶质载体家族3成员2（solute carrier family 3 member 2，Slc3a2）二聚体是嵌于胱氨酸细胞膜表面，在细胞内形成抗氧化胱氨酸/谷氨酸转运蛋白（cystine/glutamate antiporter system，System Xc⁻）［9］。System Xc⁻可促进GSH对胱氨酸的摄取合成，而GSH对Gpx4的合成至关重要，Gpx4作为能够直接还原脂质过氧化物的酶，在保护细胞免受铁死亡方面起着至关重要的作用［10］。
铁死亡抑制蛋白1（ferroptosis suppressor protein 1，Fsp1）可通过还原型烟酰胺腺嘌呤二核苷酸磷酸（nicotinamide adenine dinucleotide phosphate hydrogen，Nadph）催化辅酶q10（coenzyme q10，Coq10）的再生，对铁死亡途径发挥抑制作用［11］。当Slc7a11和Gpx4下调时，Fsp1为维持Coq10的水平，会抑制脂质过氧化的反应过程；而一旦Fsp1无法维持Coq10水平，细胞会因System Xc⁻-Gpx4轴抑制所致铁死亡易感性增加［12］。
本研究使用体外HEI-OC1细胞系实验，检验GenX暴露是否引起耳蜗毛细胞损伤，并检测是否有铁死亡的参与，进一步探索GenX暴露引起耳蜗毛细胞铁死亡信号通路中的分子机制。本研究围绕System Xc⁻-Gpx4-Fsp1轴进行研究，为防治GenX诱导的耳蜗毛细胞损伤提供了分子干预方向。
1　材料方法
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1.1　主要试剂
DMEM培养基、胎牛血清购自美国Gibco公司；小鼠耳蜗毛细胞HEI-OC1由上海第六人民医院时海波团队赠送；GenX购自上海麦克林公司；铁死亡抑制剂（ferrostatin-1，Fer-1）购自美国MCE公司；Hoechst33342、Bodipy（C11）、FerroOrange、线粒体膜电位荧光探针（mitochondrial membrane potential assay kit，JC-1）、CellTiter-Lumi™ Plus发光法细胞活力检测试剂盒、RIPA裂解缓冲液、BCA蛋白定量试剂盒、山羊抗鼠二抗和山羊抗兔二抗购自上海碧云天生物公司；CCK-8细胞活力检测试剂盒购自日本同仁公司；兔抗Gpx4购自英国Abcam公司；兔抗Slc7a11、兔抗酰基辅酶A合成酶长链家族成员4（acyl-coa synthetase long chain family member 4 gene，Acsl4）、Trizol购自美国Thermo公司；鼠抗β-actin、兔抗Gapdh、兔抗Claudin5抗体购自武汉三鹰生物公司；兔抗Fsp1、兔抗Myo7a抗体购自武汉赛维尔科技公司；SDS-PAGE凝胶电泳试剂盒购自上海雅酶生物公司；PVDF膜购自美国Invitrogen公司；反转录试剂购自日本TaKaRa公司。
1.2　细胞培养及分组
HEI-OC1细胞在含10%胎牛血清的DMEM培养基中培养，置于37 ℃、5%CO2的培养箱中维持常规培养。待细胞密度长到60%左右时，按完全随机方法分为：对照组，细胞只含培养基；GenX组，细胞加入含50、100、200 μmol/L的GenX；Fer-1组，细胞加入含0.5、1.0、5.0 μmol/L Fer-1；GenX+Fer-1组，细胞加入含200.0 μmol/L GenX和0.5 μmol/L Fer-1，共处理12 h；DMSO组，细胞加入含0.1%的DMSO溶液。其中，GenX由纯水配制为200 μmol/L储备液，Fer-1由DMSO配制为10 μmol/L储备液，按所需浓度逐步稀释到工作浓度。
1.3　CCK-8实验
在37 ℃水浴中将HEI-OC1细胞解冻并进行复苏，以1 000×g离心5 min，弃上清液，用含10%胎牛血清的DMEM培养基重悬后继续培养。按每孔约5×10³个细胞接种于96孔板中，培养24 h，分别加入对应组别的细胞培养液，设置只加CCK-8工作液的孔作为空白组，使用10%CCK-8工作液在细胞培养箱中孵育至橙黄色，以对照组吸光值达到0.8~1.0为标准。采用CCK-8细胞活力检测试剂盒测定各孔的OD值，并根据以下公式计算细胞存活率：细胞存活率=（OD实验组-OD空白组）/（OD对照组-OD空白组）×100%。
1.4　Western blot检测
用PBS对6孔板内各处理组细胞清洗2遍，每孔加入100 μL裂解液进行裂解，刮取完成蛋白溶液制备，置于冰上裂解30 min。在4 ℃下以12 000 r/min离心15 min，收集上清用于BCA蛋白定量。定量完成后，将蛋白样品在100 ℃金属水浴中煮沸10 min使蛋白充分变性。取15 μL蛋白溶液进行SDS-PAGE电泳分离，转至PVDF膜上，膜使用脱脂奶粉配制而成的TBST溶液封闭2 h。根据目的蛋白Gpx4、Ascl4、Slc7a11、Claudin5、肌球蛋白VIIA（viiamyosin viia gene，Myo7a）、Fsp1的目标蛋白的分子量进行裁剪，分别孵育对应的一抗抗体，4 ℃冰箱过夜，用TBST溶液漂洗3次。孵育相应的二抗抗体，继续TBST溶液漂洗3次，用显影仪进行蛋白曝光显影。
1.5　qRT-PCR实验
用1 mL TRIzol裂解HEI-OC1细胞，充分吹打5 min后转移至离心管。加入200 μL氯仿，充分混匀，室温静置5 min，于4 ℃、12000 r/min离心10 min，取上清置于新的1.5 mL的EP管中，加入500 μL异丙醇，充分混匀后静置10 min。再于4 ℃、12 000 r/min离心10 min后弃上清。使用75%乙醇冲洗RNA沉淀2次，待RNA沉淀透明后，加入DEPC水溶解RNA。按照TaKaRa反转录试剂说明书进行逆转录，进行qRT-PCR上机实验。使用2-ΔΔCt方法计算目的基因的相对表达。具体qRT-PCR引物序列见表1。
1.6　免疫荧光染色
将各组HEI-OC1细胞从细胞培养箱中取出，用PBS清洗3次，置于室温下4％多聚甲醛避光固定30 min，PBS再清洗3次。在37 ℃保温箱中孵育Bodipy（C11） 20 min、FerroOrange 10 min，PBS清洗3次，使用Hoechst33342对细胞核染色10 min，PBS清洗3次后，置于共聚焦显微镜下拍照观察细胞。JC-1免疫荧光染色时取出细胞，使用PBS清洗细胞1次，加入1 mL培养基，再加入配好的1 mL JC-1工作液，在细胞培养箱中孵育20 min后再用JC-1洗涤液清洗2次，在共聚焦显微镜下拍照观察细胞。
1.7　ATP检测
将细胞以5 000个/孔接种于黑色96孔板，贴壁培养24 h后加入相应组别溶液处理。作用时间结束后取出培养板，于室温静置10 min，向各孔加入100 μL CellTiter-LumiTM Plus检测试剂，振荡混匀2 min后在室温下孵育20 min，使用酶标仪检测荧光信号，并分析细胞内ATP水平。
1.8　统计学分析
使用GraphPad Prism 8.0软件完成，计量资料采用x¯±se的形式表达。两组间的差异采用LSD-t法进行检验，多组数据比较则运用单因素方差分析，P<0.05表示差异具有统计学意义。
2　结果
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2.1　GenX暴露降低耳蜗毛细胞活力
为了验证GenX暴露能否引起耳蜗毛细胞的毒性损伤，通过细胞活力值来评估GenX暴露对HEI-OC1细胞的毒性作用。结果显示，GenX浓度为200 μmol/L时，暴露12 h后细胞活力出现显著下降（P<0.01，图1）。暴露36 h时，50、100、200 μmol/L GenX处理组的细胞活力均显著降低（P<0.01，图1）。以上结果表明，随着GenX暴露时间延长及处理浓度增加，HEI-OC1细胞活力呈逐渐下降趋势，表现出典型的时间-剂量依赖性。根据实验结果选取能引起耳蜗毛细胞活力减弱的最小浓度剂量和时间暴露进行实验，故采用200 μmol/L GenX暴露12 h进一步实验。
2.2　铁死亡参与GenX毒性暴露诱导的耳蜗毛细胞损伤
为验证铁死亡是否参与GenX诱导的耳蜗毛细胞损伤，使用Fer-1处理检验能否挽救GenX暴露引起的细胞毒性。研究结果显示，0.5 μmol/L Fer-1单独处理HEI-OC1细胞12 h后对细胞活力没有影响（图2A），根据实验结果选取0.5 μmol/L Fer-1进一步实验。GenX和Fer-1联合处理后细胞活力较GenX组显著恢复（P<0.05，图2B），提示GenX暴露可诱导HEI-OC1发生铁死亡。检测各组细胞中ATP含量，结果显示GenX暴露引起HEI-OC1细胞中ATP减少，GenX+Fer-1组较GenX组能显著抑制ATP减少（P<0.001，图2C）。为检测GenX暴露是否引起Fe²⁺蓄积，对各组进行FerroOrange探针检测，结果显示GenX暴露显著促进了HEI-OC1细胞中Fe²⁺蓄积，GenX+Fer-1组中Fe²⁺含量较GenX组显著减少（图2D）。探究各组暴露后脂质过氧化物蓄积情况，对各组细胞进行Bodipy（C11）探针进行染色，结果显示GenX暴露引起HEI-OC1细胞中脂质过氧化物蓄积增多，GenX+Fer-1组较GenX组显著减少（图2E）。使用JC-1对各组细胞进行免疫荧光染色检测线粒体膜的变化情况，结果显示GenX暴露引起HEI-OC1细胞中线粒体膜电位下降，GenX+Fer-1组较GenX组能显著减轻线粒体电位下降（图2F）。
2.3　GenX通过破坏System Xc⁻-Gpx4抗氧化轴诱导耳蜗毛细胞铁死亡
本研究选取了铁死亡途径中重要的基因进行验证，包括Gpx4、Acsl4、Slc7a11、Slc3a2、溶血磷脂酰胆碱酰基转移酶3（lysophosphatidylcholine acyltransferase 3，Lpcat3）、谷胱甘肽过氧化物酶4同工酶（glutathione peroxidase 4 isozyme，mGpx4），以上基因在铁死亡通路中关系如图3A所示。实验结果显示，与Control组相比，GenX组引起HEI-OC1细胞中促铁死亡基因Acsl4、Lpcat3增加（P<0.001），抗铁死亡Gpx4、Slc7a11、Slc3a2基因表达减少（P<0.01，图3B）。GenX+Fer-1组较GenX组相比可逆转Gpx4、Slc7a11、Slc3a2、Lpcat3基因的表达（P<0.01，图3B）。同时检测了各组Gpx4、Acsl4、Slc7a11蛋白的表达水平，结果显示，与Control组相比，GenX组引起Gpx4、Slc7a11蛋白表达降低，Acsl4蛋白表达升高（P<0.01）。GenX+Fer-1组较GenX组可显著升高Gpx4、Slc7a11蛋白的表达，降低Acsl4蛋白的表达（P<0.05，图3C、D）。以上结果表明GenX暴露诱发耳蜗毛细胞抗氧化系统失衡引起铁死亡的发生。
2.4　Fer-1对GenX诱导的耳蜗毛细胞损伤具有保护作用
为研究Fer-1能否抵抗GenX暴露引起的耳蜗毛细胞分化和屏障功能损伤，本研究检测了耳蜗毛细胞自身分化基因Myo7a、溶质载体家族26成员5（solute carrier family 26 member 5 gene，Slc26a5）、Cldnb及耳蜗血迷路屏障功能基因Occludin、Claudin5、紧密连接蛋白1（zonula occludens-1，Zo-1）的表达情况。结果显示，与Control组相比，GenX组暴露降低了耳蜗毛细胞分化基因（Myo7a、Slc26a5、Cldnb）以及耳蜗血迷路屏障相关基因（Occludin、Claudin5）表达水平（P<0.05）。然而，GenX+Fer-1组较GenX组部分耳蜗毛细胞生长分化基因（Myo7a、Cldnb）和血迷路屏障功能基因（Occludin、Claudin5）的表达得到明显恢复（P<0.05，图4A、B）。同时检测了Myo7a、Claudin5蛋白的表达情况，结果显示，与Control组相比，GenX组引起Myo7a、Claudin5蛋白表达降低（P<0.01），GenX+Fer-1组较GenX组能逆转Myo7a、Claudin5蛋白的表达（P<0.01，图4C、D）。综上，研究结果表明，Fer-1能够在一定程度上拮抗GenX引起的耳蜗毛细胞损伤，改善其分化及屏障功能异常。
2.5　Fer-1调节Fsp1-Coq10-Nadph通路缓解GenX诱导的耳蜗毛细胞损伤
Fsp1、Nadph、Coq10、肝激酶B1（liver kinase B1，Lkb1）、腺苷酸活化蛋白激酶（adenosine monophosphate-activated protein kinase，Ampk）、核因子E2相关因子2（nuclear factor erythroid 2-related factor 2，Nrf2）、血红素加氧酶1（heme oxygenase 1，Ho1）等分子在调节氧化应激和抗铁死亡通路的调控中起关键作用。本研究使用qRT-PCR检测发现，与Control组相比，GenX组暴露引起Fsp1、Coq10和Nadph的基因表达水平均显著降低，而GenX+Fer-1组较GenX组可逆转其表达变化（P<0.01，图5A）。在Lkb1-Ampk、Nrf2-Ho1信号通路中GenX暴露没有引起Lkb1、Ho1基因差异表达，GenX+Fer-1组较GenX组相比Ampk、Ho1基因表达没有得到明显的逆转（图5B、C）。检测了Fsp1蛋白的表达情况，结果显示GenX组引起Fsp1蛋白表达降低，GenX+Fer-1组能逆转Fsp1蛋白的表达（P<0.05，图5D、E）。研究结果提示Fsp1-Coq10-Nadph通路可能参与了Fer-1对GenX诱导耳蜗毛细胞损伤的保护作用。
3　讨论
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3.1　GenX暴露降低耳蜗毛细胞活力
GenX作为PFAS家族的一员，具有长期残留性［13］。目前GenX可影响全身多器官病变，已引发广泛关注。有研究发现GenX暴露会导致子宫肌层细胞活力和增殖增加，增加了子宫肌瘤疾病的发病风险［14］。为研究GenX对耳蜗毛细胞的影响，选择多浓度GenX多时间点暴露研究，本研究发现50 µmol/L和100 µmol/L GenX暴露36 h时出现HEI-OC1细胞损伤，而200 µmol/L GenX暴露12 h时即出现细胞损伤。同时发现HEI-OC1细胞在同一浓度GenX暴露条件下，细胞活力随暴露时间增长而降低。这证实GenX暴露可引起耳蜗毛细胞损伤，为高风险人群（如化工工人）的听力监测与健康宣教提供依据。
3.2　铁死亡参与了GenX毒性暴露诱导的耳蜗毛细胞损伤
近年来，环境污染物通过铁死亡途径损伤耳蜗毛细胞的证据逐渐增多。已有研究表明，聚苯乙烯纳米塑料可通过抑制Gpx4和Slc7a11表达诱导脂质过氧化，从而损伤耳蜗毛细胞［15］。本研究发现GenX和Fer-1共处理后细胞活力有所改善，揭示了新型污染物GenX在HEI-OC1细胞中可能会诱导铁死亡发生。同时，本研究发现GenX暴露会表现出脂质过氧化积累、铁负荷增加、线粒体去极化与能量耗竭等关键铁死亡特征。因此，可推测GenX暴露会诱导HEI-OC1细胞铁死亡发生。
3.3　GenX通过破坏System Xc⁻-Gpx4抗氧化轴诱导耳蜗毛细胞铁死亡
目前已经公认的铁死亡途径包括：①抗铁死亡System Xc⁻-Gpx4轴通路清除氧化物失衡；②脂质过氧化引起的过氧化物蓄积引起铁死亡发生；③Fe²⁺蓄积引起铁死亡发生［16］。当System Xc⁻功能受阻或Gpx4活性下降时，脂质过氧化物无法被有效清除，并在Fe2+作用下参与芬顿反应，最终引发细胞膜结构破坏并导致细胞死亡［17］。本研究表明GenX暴露可引起System Xc⁻系统障碍，Slc3a2、Slc7a11、Gpx4抗铁死亡分子表达减少，细胞通过上调Acsl4表达促进长链多不饱和脂肪酸的酯化，增加脂质过氧化底物的生成，从而加剧铁死亡。Fer-1能够显著缓解GenX引起的细胞毒性，显著降低脂质过氧化水平，逆转GenX诱导的细胞铁死亡发生。这些结果表明，GenX对毛细胞的损伤不仅涉及铁代谢紊乱，还与脂代谢紊乱有关，为设计靶向脂代谢的铁死亡抑制策略提供了新的理论依据。
Fer-1的作用靶点是抑制脂质过氧化，从而抑制铁死亡的发生［18］。但本研究结果显示Fer-1引起了上游Gpx4的基因表达逆转，考虑为在Fer-1的作用下引起细胞脂质过氧化减轻，负调控引起Gpx4、Slc7a11、Slc3a2逆转起保护效应作用。同时，本研究结果中Acsl4分子在GenX+Fer-1组中蛋白和基因的表达相反，考虑与转录后调控等原因相关。部分基因在Fer-1处理后表达有所升高，考虑与Fer-1处理后细胞适应性反馈调节和信号通路激活的原因相关。
3.4　Fer-1对GenX诱导的耳蜗毛细胞损伤具有保护作用
耳蜗毛细胞的正常功能依赖于其内环境的稳态，内环境的维持由耳蜗血迷路屏障系统完成［19-20］。耳蜗毛细胞具有自身表达的基因，如Myo7a、Cldnb、Slc26a5等［21-23］。Myo7a是一种非传统的肌球蛋白分子马达，参与调整声音传导通道对持续刺激的敏感性［24］；Cldnb是紧密连接蛋白成员之一，它主要在耳蜗毛细胞与其周围支持细胞中表达［23］；Slc26a5也被称为Prestin蛋白，其功能是当耳蜗外毛细胞膜电位发生变化时，引起整个耳蜗外毛细胞的长度迅速缩短或伸长［25］。
本研究表明GenX暴露会影响耳蜗血迷路屏障和耳蜗毛细胞自身分化相关基因和蛋白的表达。这提示GenX对耳蜗毛细胞可能不仅限于血迷路屏障的破坏，还可能影响内耳微环境的稳态，进一步加剧听力功能障碍。当前研究仅限于基因和蛋白表达水平的变化，耳蜗血迷路屏障功能是否改变有待未来通过功能性实验进一步证实。
3.5　Fer-1调节Fsp1-Coq10-Nadph通路缓解GenX诱导的毛细胞损伤
既往研究表明，与铁死亡相关的听力损失信号通路主要包括Fsp1-Coq10-Nadph、Lkb1-Ampk、Nrf2-Ho1［26］。Fsp1-Coq10-Nadph通路是细胞抵抗脂质过氧化的第二道防线［12］。既往研究表明，耳毒性药物顺铂会引起该信号通路受损，削弱这条抗铁死亡通路的防御能力［27］。在本研究中，GenX暴露同样引起耳蜗毛细胞Fsp1表达下调，导致Coq10再生障碍，加重脂质过氧化，引起铁死亡的发生。Lkb1-Ampk通路通过调控细胞代谢来影响铁死亡的敏感性，当细胞遭受损伤时，细胞中ATP会被消耗，间接激活该通路［28-29］。Nrf2-Ho1通路是细胞抗氧化的主要调节通路，在应激条件下，该通路的过度激活可能导致铁代谢失衡［30］。
在本研究中GenX暴露会诱导耳蜗毛细胞Slc7a11和Gpx4下调，引起Fsp1、Coq10、Nadph基因表达下降，这使得耳蜗毛细胞对脂质过氧化物更加敏感，极易触发铁死亡，可能进一步导致不可逆的听力损失，但GenX+Fer-1会逆转上述基因的表达。提示Fer-1可通过调节Fsp1-Coq10-Nadph通路缓解GenX诱导的耳蜗毛细胞损伤。
综上所述，本研究表明GenX通过依赖System Xc⁻- Gpx4-Fsp1铁死亡轴途径损伤耳蜗毛细胞自身分化和屏障功能，Fer-1可以逆转GenX暴露引起的铁死亡发生，从而保护耳蜗毛细胞自身分化和屏障功能。本研究为预防GenX暴露引起的耳蜗毛细胞损伤提供了分子干预方向和药物靶点。未来的研究将进行动物实验行体内验证，具体调控机制仍需通过基因编辑技术深入验证。同时，对System Xc⁻-Gpx4-Fsp1轴进行功能验证也是未来的重要研究方向。

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doi: 10.16016/j.2097-0927.202507094
  • 接收时间：2025-07-28
  • 首发时间：2026-10-30
  • 出版时间：2025-11-15
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  • 收稿日期：2025-07-28
  • 修回日期：2025-10-23
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    1西南医科大学附属医院耳鼻咽喉头颈外科，四川 泸州
    2重庆市人民医院（重庆大学附属人民医院）耳鼻咽喉头颈外科，重庆
    3重庆大学医学院神经智能中心实验室，重庆

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